Antibiofilm Synergy of β-Lactams and Branched Polyethylenimine against Methicillin-Resistant Staphylococcus epidermidis

Abstract

Microbial biofilms are ubiquitous in nature, and they pose a serious threat to public health. Staphylococcus epidermidis is the most common clinical isolate from healthcare-and medical device-related biofilm infections. No antibiotic currently on the market can eradicate pathogenic biofilms, which contain complex defense mechanisms composed of slimelike extracellular polymeric substances. Understanding the need to develop alternative approaches, we examine 600 Da branched polyethylenimine (BPEI) against methicillin-resistant Staphylococcus epidermidis (MRSE) bio-films. Here, a microtiter biofilm model is used to test the synergistic effects between the two components of our combination treatment: BPEI and β-lactam antibiotics. Electron microscopy was used to confirm the growth of MRSE biofilms from the model. Minimum biofilm eradication concentration assays, crystal violet assays, and biofilm kill curves suggest that BPEI exhibits antibiofilm activity and can potentiate β-lactams to eradicate MRSE biofilms.

PEGylation of Polyethylenimine Lowers Acute Toxicity while Retaining Anti-Biofilm and β-Lactam Potentiation Properties against Antibiotic-Resistant Pathogens

“…The oxacillin MBEC drops to 16 μg/mL in the presence of 13 μM 600 Da BPEI. 13 However, this 13 μM 600 Da BPEI does not dissolve the biofilm according to the crystal violet assay. Rather, 214 μM 600 Da BPEI are required to disperse the biofilm EPS into the solution.…”

“…Bacterial cells that remain after cleansing survive antibiotic therapy, quickly populate the wound bed, and regenerate the biofilm matrix. An advantage of 600 Da BPEI is its ability to disrupt biofilms of staphylococci 12 , 13 , 48 and P. aeruginosa . 4 PEGylated 600 Da BPEI retains these anti-biofilm properties and is a superior anti-biofilm agent compared to non-PEGylated 600 Da BPEI.…”

“…The biofilm is dissolved with 214 μM (128 μg/mL) 600 Da BPEI, consistent with a previous report where 214 μM 600 Da BPEI dissolved twice as much MRSE 35984 biofilm as 53 (32 μg/mL) and 106 μM (64 μg/mL) 600 Da BPEI. 13 Adding 350 MW PEG to 600 Da BPEI improves its anti-biofilm properties. The MRSE 35984 biofilm is completely dispersed by 67.4 μM (PEG-350) 1 -(BPEI-600) 1 , a concentration that is 3.6 times lower than the 214 μM 600 Da BPEI required to give the same results.…”

“…Eradication of MRSE biofilms requires a higher amount of oxacillin, MBEC = 512 μg/mL, because of barriers imposed by the biofilm EPS. 13 However, 600 Da BPEI can weaken the EPS to increase oxacillin activity without dissolving the EPS. The oxacillin MBEC drops to 16 μg/mL in the presence of 13 μM 600 Da BPEI.…”

Self-targeting, zwitterionic micellar dispersants enhance antibiotic killing of infectious biofilms—An intravital imaging study in mice

“…Cationic nanoparticles are often unable to penetrate into a biofilm but accumulate at its surface ( 36 ), while anionic and neutral nanoparticles neither penetrate in nor adsorb to the biofilm and are easily rinsed out ( 37 ). Although cationic micelles can disrupt biofilms ( 38 , 39 ), they lack the ability to self-target biofilm inhabitants. Mixed-shell polymeric micelles (MSPMs) composed of a poly(ethylene glycol) (PEG) shell and a pH-responsive poly(β-amino ester) have previously been demonstrated to perform very well in vitro and in vivo as antimicrobial nanocarriers, which could be transported through the blood owing to their stealth properties ( 40 , 41 ).…”